2011
Okajima Y, Ohno Y, Washko GR, Hatabu H.
Assessment of pulmonary hypertension what CT and MRI can provide. Acad Radiol 2011;18(4):437-53.
AbstractRATIONALES AND OBJECTIVES: Pulmonary hypertension (PH) is a life-threatening condition, characterized by elevated pulmonary arterial pressure, which is confirmed based on invasive right heart catheterization (RHC). Noninvasive examinations may support diagnosis of PH before proceeding to RHC and play an important role in management and treatment of the disease. Although echocardiography is considered a standard tool in diagnosis, recent advances have made computed tomography (CT) and magnetic resonance (MR) imaging promising tools, which may provide morphologic and functional information. In this article, we review image-based assessment of PH with a focus on CT and MR imaging.
CONCLUSIONS: CT may provide useful morphologic information for depicting PH and seeking for underlying diseases. With the accumulated technological advancement, CT and MRI may provide practical tools for not only morphologic but also functional assessment of patients with PH.
Albert RK, Connett J, Bailey WC, Casaburi R, Cooper AJD, Criner GJ, Curtis JL, Dransfield MT, Han MLK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR.
Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365(8):689-98.
AbstractBACKGROUND: Acute exacerbations adversely affect patients with chronic obstructive pulmonary disease (COPD). Macrolide antibiotics benefit patients with a variety of inflammatory airway diseases.
METHODS: We performed a randomized trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD who had an increased risk of exacerbations but no hearing impairment, resting tachycardia, or apparent risk of prolongation of the corrected QT interval.
RESULTS: A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. The rate of 1-year follow-up was 89% in the azithromycin group and 90% in the placebo group. The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P<0.001). The frequency of exacerbations was 1.48 exacerbations per patient-year in the azithromycin group, as compared with 1.83 per patient-year in the placebo group (P=0.01), and the hazard ratio for having an acute exacerbation of COPD per patient-year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P<0.001). The scores on the St. George's Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8±12.8 vs. 0.6±11.4, P=0.004); the percentage of participants with more than the minimal clinically important difference of -4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P=0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P=0.04).
CONCLUSIONS: Among selected subjects with COPD, azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing decrements in a small percentage of subjects. Although this intervention could change microbial resistance patterns, the effect of this change is not known. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00325897.).
Han MLK, Kazerooni EA, Lynch DA, Liu LX, Murray S, Curtis JL, Criner GJ, Kim V, Bowler RP, Hanania NA, Anzueto AR, Make BJ, Hokanson JE, Crapo JD, Silverman EK, Martinez FJ, Washko GR.
Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011;261(1):274-82.
AbstractPURPOSE: To test the hypothesis-given the increasing emphasis on quantitative computed tomographic (CT) phenotypes of chronic obstructive pulmonary disease (COPD)-that a relationship exists between COPD exacerbation frequency and quantitative CT measures of emphysema and airway disease.
MATERIALS AND METHODS: This research protocol was approved by the institutional review board of each participating institution, and all participants provided written informed consent. One thousand two subjects who were enrolled in the COPDGene Study and met the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD with quantitative CT analysis were included. Total lung emphysema percentage was measured by using the attenuation mask technique with a -950-HU threshold. An automated program measured the mean wall thickness and mean wall area percentage in six segmental bronchi. The frequency of COPD exacerbation in the prior year was determined by using a questionnaire. Statistical analysis was performed to examine the relationship of exacerbation frequency with lung function and quantitative CT measurements.
RESULTS: In a multivariate analysis adjusted for lung function, bronchial wall thickness and total lung emphysema percentage were associated with COPD exacerbation frequency. Each 1-mm increase in bronchial wall thickness was associated with a 1.84-fold increase in annual exacerbation rate (P = .004). For patients with 35% or greater total emphysema, each 5% increase in emphysema was associated with a 1.18-fold increase in this rate (P = .047).
CONCLUSION: Greater lung emphysema and airway wall thickness were associated with COPD exacerbations, independent of the severity of airflow obstruction. Quantitative CT can help identify subgroups of patients with COPD who experience exacerbations for targeted research and therapy development for individual phenotypes.
Kim DK, Jacobson FL, Washko GR, Casaburi R, Make BJ, Crapo JD, Silverman EK, Hersh CP.
Clinical and radiographic correlates of hypoxemia and oxygen therapy in the COPDGene study. Respir Med 2011;105(8):1211-21.
AbstractBACKGROUND: Severe hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD). Long-term oxygen therapy is beneficial in hypoxemic COPD patients. However, the clinical and radiographic predictors of hypoxemia and the use of oxygen therapy are not well described. This study aimed to find the correlates of resting hypoxemia and the pattern of oxygen use in moderate to severe COPD patients.
METHODS: Subjects with GOLD stage II or higher COPD from the first 2500 COPDGene subjects were included in this analysis. All subjects were current or ex-smokers between ages 45 and 80. Severe resting hypoxemia was defined as room air oxygen saturation (SpO(2)) ≤88%. Use of supplemental oxygen therapy was determined by questionnaire.
RESULTS: Eighty-two of 1060 COPD subjects (7.7%) had severe resting hypoxemia. Twenty-one of the 82 (25.6%) were not using continuous supplemental oxygen. Female sex, higher BMI, lower FEV(1), and enrollment in Denver were independent risk factors for hypoxemia; emphysema severity on quantitative chest CT scan did not predict hypoxemia. 132 of 971(13.6%) subjects without severe resting hypoxemia were using continuous supplemental oxygen. In non-hypoxemic oxygen users, Denver recruitment, higher BMI, lower FEV(1), and more severe dyspnea were associated with the use of continuous oxygen.
CONCLUSIONS: A large number of COPD patients without severe hypoxemia were using supplemental oxygen therapy and the pattern of oxygen use was affected by factors other than resting SpO(2) and emphysema severity. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup.
CLINICAL TRIAL REGISTRATION:
http://clinicaltrials.gov (NCT00608764).
Kim DK, Hersh CP, Washko GR, Hokanson JE, Lynch DA, Newell JD, Murphy JR, Crapo JD, Silverman EK.
Epidemiology, radiology, and genetics of nicotine dependence in COPD. Respir Res 2011;12:9.
AbstractBACKGROUND: Cigarette smoking is the principal environmental risk factor for developing COPD, and nicotine dependence strongly influences smoking behavior. This study was performed to elucidate the relationship between nicotine dependence, genetic susceptibility to nicotine dependence, and volumetric CT findings in smokers.
METHODS: Current smokers with COPD (GOLD stage ≥ 2) or normal spirometry were analyzed from the COPDGene Study, a prospective observational study. Nicotine dependence was determined by the Fagerstrom test for nicotine dependence (FTND). Volumetric CT acquisitions measuring the percent of emphysema on inspiratory CT (% of lung <-950 HU) and gas trapping on expiratory CT (% of lung <-856 HU) were obtained. Genotypes for two SNPs in the CHRNA3/5 region (rs8034191, rs1051730) previously associated with nicotine dependence and COPD were analyzed for association to COPD and nicotine dependence phenotypes.
RESULTS: Among 842 currently smoking subjects (335 COPD cases and 507 controls), 329 subjects (39.1%) showed high nicotine dependence. Subjects with high nicotine dependence had greater cumulative and current amounts of smoking. However, emphysema severity was negatively correlated with the FTND score in controls (ρ = -0.19, p < .0001) as well as in COPD cases (ρ = -0.18, p = 0.0008). Lower FTND score, male gender, lower body mass index, and lower FEV1 were independent risk factors for emphysema severity in COPD cases. Both CHRNA3/5 SNPs were associated with FTND in current smokers. An association of genetic variants in CHRNA3/5 with severity of emphysema was only found in former smokers, but not in current smokers.
CONCLUSIONS: Nicotine dependence was a negative predictor for emphysema on CT in COPD and control smokers. Increased inflammation in more highly addicted current smokers could influence the CT lung density distribution, which may influence genetic association studies of emphysema phenotypes.
Obstein KL, Patil VD, Jayender J, San José Estépar R, Spofford IS, Lengyel BI, Vosburgh KG, Thompson CC.
Evaluation of colonoscopy technical skill levels by use of an objective kinematic-based system. Gastrointest Endosc 2011;73(2):315-21, 321.e1.
AbstractBACKGROUND: Colonoscopy requires training and experience to ensure accuracy and safety. Currently, no objective, validated process exists to determine when an endoscopist has attained technical competence. Kinematics data describing movements of laparoscopic instruments have been used in surgical skill assessment to define expert surgical technique. We have developed a novel system to record kinematics data during colonoscopy and quantitatively assess colonoscopist performance.
OBJECTIVE: To use kinematic analysis of colonoscopy to quantitatively assess endoscopic technical performance.
DESIGN: Prospective cohort study.
SETTING: Tertiary-care academic medical center.
POPULATION: This study involved physicians who perform colonoscopy.
INTERVENTION: Application of a kinematics data collection system to colonoscopy evaluation.
MAIN OUTCOME MEASUREMENTS: Kinematics data, validated task load assessment instrument, and technical difficulty visual analog scale.
RESULTS: All 13 participants completed the colonoscopy to the terminal ileum on the standard colon model. Attending physicians reached the terminal ileum quicker than fellows (median time, 150.19 seconds vs 299.86 seconds; p<.01) with reduced path lengths for all 4 sensors, decreased flex (1.75 m vs 3.14 m; P=.03), smaller tip angulation, reduced absolute roll, and lower curvature of the endoscope. With performance of attending physicians serving as the expert reference standard, the mean kinematic score increased by 19.89 for each decrease in postgraduate year (P<.01). Overall, fellows experienced greater mental, physical, and temporal demand than did attending physicians.
LIMITATION: Small cohort size.
CONCLUSION: Kinematic data and score calculation appear useful in the evaluation of colonoscopy technical skill levels. The kinematic score appears to consistently vary by year of training. Because this assessment is nonsubjective, it may be an improvement over current methods for determination of competence. Ongoing studies are establishing benchmarks and characteristic profiles of skill groups based on kinematics data.
Hersh CP, Hokanson JE, Lynch DA, Washko GR, Make BJ, Crapo JD, Silverman EK.
Family history is a risk factor for COPD. Chest 2011;140(2):343-350.
AbstractBACKGROUND: Studies have shown that family history is a risk factor for COPD, but have not accounted for family history of smoking. Therefore, we sought to identify the effects of family history of smoking and family history of COPD on COPD susceptibility.
METHODS: We compared 821 patients with COPD to 776 control smokers from the Genetic Epidemiology of COPD (COPDGene) Study. Questionnaires captured parental histories of smoking and COPD, as well as childhood environmental tobacco smoke (ETS) exposure. Socioeconomic status was defined by educational achievement.
RESULTS: Parental history of smoking (85.5% case patients, 82.9% control subjects) was more common than parental history of COPD (43.0% case patients, 30.8% control subjects). In a logistic regression model, parental history of COPD (OR, 1.73; P < .0001) and educational level (OR, 0.48 for some college vs no college; P < .0001) were significant predictors of COPD, but parental history of smoking and childhood ETS exposure were not significant. The population-attributable risk from COPD family history was 18.6%. Patients with COPD with a parental history had more severe disease, with lower lung function, worse quality of life, and more frequent exacerbations. There were nonsignificant trends for more severe emphysema and airway disease on quantitative chest CT scans.
CONCLUSIONS: Family history of COPD is a strong risk factor for COPD, independent of family history of smoking, personal lifetime smoking, or childhood ETS exposure. Although further studies are required to identify genetic variants that influence COPD susceptibility, clinicians should question all smokers, especially those with known or suspected COPD, regarding COPD family history.
Yamashiro T, San José Estépar R, Matsuoka S, Bartholmai BJ, Ross JC, Diaz A, Murayama S, Silverman EK, Hatabu H, Washko GR.
Intrathoracic tracheal volume and collapsibility on inspiratory and end-expiratory ct scans correlations with lung volume and pulmonary function in 85 smokers. Acad Radiol 2011;18(3):299-305.
AbstractRATIONALE AND OBJECTIVES: To evaluate the correlations of tracheal volume and collapsibility on inspiratory and end-expiratory computed tomography (CT) with lung volume and with lung function in smokers.
MATERIALS AND METHODS: The institutional review board approved this study at each institution. 85 smokers (mean age 68, range 45-87 years; 40 females and 45 males) underwent pulmonary function tests and chest CT at full inspiration and end-expiration. On both scans, intrathoracic tracheal volume and lung volume were measured. Collapsibility of the trachea and the lung was expressed as expiratory/inspiratory (E/I) ratios of these volumes. Correlations of the tracheal measurements with the lung measurements and with lung function were evaluated by the linear regression analysis.
RESULTS: Tracheal volume showed moderate or strong, positive correlations with lung volume on both inspiratory (r = 0.661, P < .0001) and end-expiratory (r = 0.749, P < .0001) scans. The E/I ratio of tracheal volume showed a strong, positive correlation with the E/I ratio of lung volume (r = 0.711, P < .0001). A weak, negative correlation was found between the E/I ratio of tracheal volume and the ratio of forced expiratory volume in the first second to forced vital capacity (r = -0.436, P < .0001). Also, a weak, positive correlation was observed between the E/I ratio of tracheal volume and the ratio of residual volume to total lung capacity (r = 0.253, P = .02).
CONCLUSIONS: Tracheal volume and collapsibility, measured by inspiratory and end-expiratory CT scans, is related to lung volume and collapsibility. The highly collapsed trachea on end-expiratory CT does not indicate more severe airflow limitation or air-trapping in smokers.
Yamashiro T, Matsuoka S, San José Estépar R, Bartholmai BJ, Diaz A, Ross JC, Murayama S, Silverman EK, Hatabu H, Washko GR.
Kurtosis and skewness of density histograms on inspiratory and expiratory CT scans in smokers. COPD 2011;8(1):13-20.
AbstractThe aim of this study is to evaluate the relationship between lung function and kurtosis or skewness of lung density histograms on computed tomography (CT) in smokers. Forty-six smokers (age range 46?81 years), enrolled in the Lung Tissue Research Consortium, underwent pulmonary function tests (PFT) and chest CT at full inspiration and full expiration. On both inspiratory and expiratory scans, kurtosis and skewness of the density histograms were automatically measured by open-source software. Correlations between CT measurements and lung function were evaluated by the linear regression analysis. Although no significant correlations were found between inspiratory kurtosis or skewness and PFT results, expiratory kurtosis significantly correlated with the following: the percentage of predicted value of forced expiratory volume in the first second (FEV(1)), the ratio of FEV(1) to forced vital capacity (FVC), and the ratio of residual volume (RV) to total lung capacity (TLC) (FEV(1)%predicted, R = -0.581, p < 0.001; FEV(1)/FVC, R = -0.612, p < 0.001; RV/TLC, R = 0.613, p < 0.001, respectively). Similarly, expiratory skewness showed significant correlations with PFT results (FEV(1)%predicted, R = -0.584, p < 0.001; FEV(1)/FVC, R = -0.619, p < 0.001; RV/TLC, R = 0.585, p < 0.001, respectively). Also, the expiratory/inspiratory (E/I) ratios of kurtosis and skewness significantly correlated with FEV(1)%predicted (p < 0.001), FEV(1)/FVC (p < 0.001), RV/TLC (p < 0.001), and the percentage of predicted value of diffusing capacity for carbon monoxide (kurtosis E/I ratio, p = 0.001; skewness E/I ratio, p = 0.03, respectively). We conclude therefore that expiratory values and the E/I ratios of kurtosis and skewness of CT densitometry reflect airflow limitation and air-trapping. Higher kurtosis or skewness on expiratory CT scan indicates more severe conditions in smokers.
Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, Ross JC, San José Estépar R, Lynch DA, Brehm JM, Andriole KP, Diaz AA, Khorasani R, D'Aco K, Sciurba FC, Silverman EK, Hatabu H, Rosas IO.
Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 2011;364(10):897-906.
AbstractBACKGROUND: Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known.
METHODS: We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema.
RESULTS: Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (-0.444 liters; 95% confidence interval [CI], -0.596 to -0.292; P<0.001) and a lower percentage of emphysema defined by lung-attenuation thresholds of -950 Hounsfield units (-3%; 95% CI, -4 to -2; P<0.001) and -910 Hounsfield units (-10%; 95% CI, -12 to -8; P<0.001). As compared with participants without interstitial lung abnormalities, those with abnormalities were more likely to have a restrictive lung deficit (total lung capacity <80% of the predicted value; odds ratio, 2.3; 95% CI, 1.4 to 3.7; P<0.001) and were less likely to meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking.
CONCLUSIONS: In smokers, interstitial lung abnormalities--which were present on about 1 of every 12 HRCT scans--were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation; ClinicalTrials.gov number, NCT00608764.).
Risholm P, Ross J, Washko GR, Wells WM.
Probabilistic elastography: estimating lung elasticity. Inf Process Med Imaging 2011;22:699-710.
AbstractWe formulate registration-based elastography in a probabilistic framework and apply it to study lung elasticity in the presence of emphysematous and fibrotic tissue. The elasticity calculations are based on a Finite Element discretization of a linear elastic biomechanical model. We marginalize over the boundary conditions (deformation) of the biomechanical model to determine the posterior distribution over elasticity parameters. Image similarity is included in the likelihood, an elastic prior is included to constrain the boundary conditions, while a Markov model is used to spatially smooth the inhomogeneous elasticity. We use a Markov Chain Monte Carlo (MCMC) technique to characterize the posterior distribution over elasticity from which we extract the most probable elasticity as well as the uncertainty of this estimate. Even though registration-based lung elastography with inhomogeneous elasticity is challenging due the problem's highly underdetermined nature and the sparse image information available in lung CT, we show promising preliminary results on estimating lung elasticity contrast in the presence of emphysematous and fibrotic tissue.
Woodruff PG, Albert RK, Bailey WC, Casaburi R, Connett JE, Cooper JAD, Criner GJ, Curtis JL, Dransfield MT, Han MLK, Harnden SM, Kim V, Marchetti N, Martinez FJ, McEvoy CE, Niewoehner DE, Reilly JJ, Rice K, Scanlon PD, Scharf SM, Sciurba FC, Washko GR, Lazarus SC.
Randomized trial of zileuton for treatment of COPD exacerbations requiring hospitalization. COPD 2011;8(1):21-9.
AbstractRATIONALE: Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations.
OBJECTIVE: We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization.
METHODS: Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production.
MAIN FINDINGS: Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75 +/- 2.19 vs. 3.86 +/- 3.06 days for zileuton vs. placebo, p = 0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p = 0.63) despite a decline in urinary LTE(4) levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine -1.38 +/- 1.19 vs. 0.14 +/- 1.51, p < 0.0001) and 72 hours (-1.32 +/- 2.08 vs. 0.26 +/- 1.93, p<0.006). Adverse events were similar in both groups.
PRINCIPAL CONCLUSIONS: While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE(4) levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.
Matsuoka S, Yamashiro T, Diaz A, San José Estépar R, Ross JC, Silverman EK, Kobayashi Y, Dransfield MT, Bartholmai BJ, Hatabu H, Washko GR.
The relationship between small pulmonary vascular alteration and aortic atherosclerosis in chronic obstructive pulmonary disease: quantitative CT analysis. Acad Radiol 2011;18(1):40-6.
AbstractRATIONALE AND OBJECTIVES: The relationship between chronic obstructive pulmonary disease (COPD) and atherosclerosis has been suggested; this association may relate to systemic inflammation and endothelial dysfunction, which can lead to alteration of small pulmonary vessels. The relationship between atherosclerosis and small pulmonary vessel alteration, however, has not been assessed in COPD patients. We tested the hypothesis that the severity of thoracic aortic calcification measured by computed tomography (CT) would be associated with the total cross-sectional area of small pulmonary vessels (CSA) on CT images.
MATERIALS AND METHODS: The study was approved by the institutional review board and was Health Insurance Portability and Accountability Act-compliant. Informed consent was waived. For 51 COPD patients enrolled in the National Heart, Lung, and Blood Institute Lung Tissue Research Consortium, we calculated the percentage of total CSAs of less than 5 mm² for the total lung area (%CSA<5). Thoracic aortic calcification, quantified by modified Agatston score, was measured. The correlations between thoracic aortic calcification score and %CSA<5, pulmonary function, and extent of emphysema were evaluated. Multiple linear regression analysis using aortic calcification score as the dependent outcome was also performed.
RESULTS: The %CSA<5 had a significant negative correlation with the thoracic aortic calcification score (r = -0.566, P < .0001). Multiple linear regression analysis showed significant correlation between the aortic calcification score and %CSA<5 (P < .0001) independent of age, pack-years, extent of emphysema, and FEV1%.
CONCLUSIONS: Atherosclerosis, assessed by aortic calcification, is associated with the small pulmonary vascular alteration in COPD. Systemic inflammation and endothelial dysfunction may cause the close relationship between atherosclerosis and small pulmonary vessel alteration.
